Over 90 individual human papilloma virus types (HPV) have been described. Genital HPV infection in young, sexually active women is common and most infected individuals either clear the infection, or if lesions do develop, have regression of the lesions. Only a subset of infected individuals develop lesions which progress to a high grade, intraepithelial neoplasia and only a fraction of the intraepithelial neoplasias progress to invasive carcinoma.
Carcinoma of the cervix in a woman develops through a pre-cancerous, intermediate stage to an invasive carcinoma which frequently leads to death. Infection of genital epithelial cells with human papilloma virus (HPV) types 16 and 18 is closely associated with the development of cervical carcinoma. The HPV genome encodes 7 early (E) nonstructural regulatory proteins and two late (L) structural proteins. Integration of the viral DNA in the genome of the host cell, which is considered an essential step in HPV16- or HPV18-induced development of cervical carcinoma, results in a loss of E1- or E2-mediated transcriptional control. As a consequence, the transformed cells over-express the E6 and E7 proteins, thus initiating the malignant transformation process (Pei, Carcinogenesis 1996, 17:1395–1401).
Specific cell-mediated immunity is believed to play an essential role in the control of HPV infections and cervical carcinoma. This assumption is based on observations showing (i) that HPV-induced lesions spontaneously regress in the majority of individuals, and (ii) that immunodeficient patients develop significantly more HPV related proliferative lesions in skin and anogenital tissue than immunocompetent individuals. It has been demonstrated in several animal models that the HPV E6 and E7 proteins, constitutively expressed in HPV transformed cells, can act as targets for CTL-mediated tumor cell killing and stimulation of tumor-specific CTL activity. Induction of an antigen-specific CTL response requires intracellular processing of the target antigen and presentation of antigenic peptides by MHC class I molecules.
In the last few years, a number of peptide/protein-based or genetic immunization strategies have been described for the induction of HPV-specific CTL activity. Drawbacks associated with the peptide-based approach include MHC-polymorphism and the risk of inducing T-cell tolerance rather than T-cell activation. Due to the induction of specific T-cell tolerance, vaccination with a tumor-specific peptide has been shown to result in an enhanced outgrowth of the tumor. Immunization with larger proteins would overcome these problems, but requires efficient antigen delivery systems and/or safe adjuvants for efficient immune priming.
The induction of HPV-specific CTL responses in mice upon immunization with recombinant vaccinia virus that expresses HPV E6 or E7 unexpectedly produced lower titers compared to the parental strain that seriously reduces the effectiveness for inducing HPV-specific CTL responses. Other drawbacks associated with the use of the vaccinia virus-based vector system include immune responses against viral proteins in pre-immune patients or more seriously, integration of recombinant genes into the host cell genome (retrovirus). The risk of integration into the host cell genome is a point of major concern as infected cells can indeed survive and become tumorigenic (immortalized), especially when the recombinant virus encodes oncoproteins such as HPV E6 or E7